1. Anti-inflammatory effects of limb ischaemic preconditioning are mediated by sensory nerve activation in rats.
- Author
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Hartmann P, Varga R, Zobolyák Z, Héger J, Csosz B, Németh I, Rázga Z, Vízler C, Garab D, Sántha P, Jancsó G, Boros M, and Szabó A
- Subjects
- Animals, Calcitonin Gene-Related Peptide therapeutic use, Cell Adhesion drug effects, Diterpenes therapeutic use, Humans, Intercellular Adhesion Molecule-1 metabolism, Leukocyte Rolling drug effects, Leukocytes cytology, Leukocytes drug effects, Male, Microcirculation drug effects, Microscopy, Video, Nerve Fibers drug effects, Nerve Fibers metabolism, Neurons, Afferent drug effects, Neurons, Afferent metabolism, Peptide Fragments therapeutic use, Periosteum blood supply, Periosteum immunology, Periosteum metabolism, Rats, Rats, Sprague-Dawley, Reperfusion Injury blood, Reperfusion Injury immunology, Reperfusion Injury metabolism, Sensory Receptor Cells metabolism, Venules drug effects, Venules metabolism, Calcitonin Gene-Related Peptide Receptor Antagonists, Hindlimb blood supply, Ischemic Preconditioning methods, Receptors, Calcitonin Gene-Related Peptide agonists, Reperfusion Injury prevention & control, Sensory Receptor Cells drug effects
- Abstract
We have shown that ischaemic preconditioning ameliorates both the local periosteal and the systemic leukocyte activation evoked by limb ischaemia-reperfusion. We hypothesized that the activation of chemosensitive afferent nerves by transient ischaemia contributes to the protective mechanisms of ischaemic preconditioning via a calcitonin gene-related peptide (CGRP)-dependent mechanism. In Sprague-Dawley rats, 60-min complete limb ischaemia was followed by 180 min of reperfusion. In further experiments, the CGRP analogue hCGRP (0.3 μg kg(-1)) or ischaemic preconditioning (2 × 10-min ischaemia/10-min reperfusion) was applied prior to the ischaemia-reperfusion insult. Ischaemic preconditioning was performed in three subgroups in which animals received the CGRP receptor antagonist CGRP(8-37) (30 μg kg(-1) h(-1)), the chemosensitive afferent nerve inactivator resiniferatoxin (3 × 15 μg kg(-1), sc), or vehicle. The effects of CGRP(8-37) and resiniferatoxin on ischaemia-reperfusion without ischaemic preconditioning were also evaluated. In the tibial periosteum of rats, intravital fluorescence microscopy and immunohistochemistry revealed significant attenuations of ischaemia-reperfusion-induced post-ischaemic leukocyte-endothelial interactions (rolling and adherence in the postcapillary venules) and tissue intracellular adhesion molecule expression following ischaemic preconditioning or hCGRP administration. Administration of CGRP(8-37) or pretreatment of animals with resiniferatoxin reversed the anti-inflammatory effects of limb ischaemic preconditioning, but failed to affect the microcirculatory consequences of ischaemia-reperfusion without ischaemic preconditioning. The results suggest that activation of the chemo- (capsaicin-) sensitive afferent nerves is involved in the mechanisms of microcirculatory anti-inflammatory protection provided by limb ischaemic preconditioning. Controlled activation of chemosensitive C-fibres or the CGRP receptors by the induction of ischaemic preconditioning or other means may furnish therapeutic benefit by ameliorating the periosteal microcirculatory consequences of tourniquet ischaemia.
- Published
- 2011
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